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Genomic variants associated with age at diagnosis of childhood-onset type 1 diabetes

Journal of Human Genetics (2024)Cite this article

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Abstract

Age at diagnosis (AAD) of Type 1 diabetes (T1D) is determined by the age at onset of the autoimmune attack and by the rate of beta cell destruction that follows. Twin studies found that T1D AAD is strongly influenced by genetics, notably in young children. In young UK, Finnish, Sardinian patients AAD-associated genomic variants were previously identified, which may vary across populations and with time. In 1956 children of European ancestry born in mainland France in 1980-2008 who declared T1D before 15 years, we tested 94 T1D-associated SNPs for their association with AAD using nonparametric Kruskal–Wallis test. While high-risk HLA genotypes were not found to be associated with AAD, fourteen SNPs located in 12 non-HLA loci showed a strong association (2.9 × 10−12 < P < 1.4 × 10−3 after FDR correction). Four of these loci have been associated with AAD in previous cohorts (GSDMB, IL2, TNFAIP3, IL1), supporting a partially shared genetic influence on AAD of T1D in the studied European populations. In contrast, the association of 8 new loci CLEC16A, TYK2, ERBB3, CCR7, FCRL3, DNAH2, FGF3/4, and HPSE2 with AAD is novel. The 12 protein-coding genes located within these loci are involved in major immune pathways or in predisposition to other autoimmune diseases, which suggests a prominent role for these genes in the early immune mechanisms of beta cell destruction.

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Acknowledgements

The diabetes centers and doctors who contributed to the Isis cohort are listed in Supplementary Table 1. We thank B. Aboumrad+, P. Lucchini and all nurses in Isis-Diab centers. We thank the patients and parents who participated in the study. We thank A. Fourreau, G. Leprun, A. Guégan and V. Jauffret for collecting samples and data, C. Mille and D Boudia for technical help.

Funding

The Isis-Diab study was sponsored by a joint 2009-2014 “Alliance Isis-Diab” grant from INSERM under the aegis of former director Christian Bréchot, and the French affiliate of the NovoNordisk Foundation under the aegis of Stéphane Calmar. The Isis-Diab cohort was also supported by the Programme Hospitalier de Recherche Clinique (PHRC) of the French Health Ministry, the Association pour la Recherche sur le Diabète (ARD) and GETDOC Association.

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Authors and Affiliations

  1. Inserm U1169, now at MIRCEN, Commissariat à l’Énergie Atomique, Fontenay-aux-Roses, France

    Pierre Bougnères, Sophie Le Fur, Thanh-Nga Mai, Marie-Pierre Belot & Alain-Jacques Valleron

  2. GETDOC Association, Paris, France

    Pierre Bougnères, Sophie Le Fur & Marie-Pierre Belot

  3. Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN Center now at the Graduate School of Frontier Sciences, Tokyo University, Tokyo, Japan

    Yoichiro Kamatani

  4. Service d’Endocrinologie Diabétologie Pédiatrique, Hôpital Mère-Enfant, Lyon, France

    Kevin Perge

  5. Digital Technologies Research Center, National Research Council Canada, Ottawa, ON, K1A 0R6, Canada

    XiaoJian Shao

  6. Genome Québec Innovation Centre, Quantitative Life Sciences, McGill University, Montréal, QC, Canada

    Mark Lathrop

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  1. Pierre Bougnères
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  9. Alain-Jacques Valleron
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the Isis-Diab group

Contributions

PB designed the study, analyzed the data, and drafted the manuscript. AJV supervised statistical analyses. SLF organized the study protocol, data and sample collection, and data interpretation. TNM performed statistical analyses. YK performed genomic imputations. XS did the GO and pathway analyses. Clinicians of the Isis-Diab group and KP recruited the patients. MPB performed SNP genotyping using PCR-based techniques. ML organized GWAS and supervised genomic analyses.

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Correspondence to Pierre Bougnères.

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Bougnères, P., Le Fur, S., Kamatani, Y. et al. Genomic variants associated with age at diagnosis of childhood-onset type 1 diabetes. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01272-3

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